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Liver disease is the fifth most common cause of death worldwide. Transplantation offers a treatment, but not enough livers are available for transplantation. Scientists are therefore searching for other ways to tackle liver disease and save lives. Professor Mathieu Vinken and his team on VUB’s Jette Campus are a driving force behind this lofty ambition.

 

It’s 5.30 am at the VUB Life Science Campus in northwest Brussels ‑ silence reigns. A dim light gleams through the darkness. It shines from the window of the Department of In Vitro Toxicology and Dermato-Cosmetology. This is the most productive time of the day for 37-year-old Professor Mathieu Vinken.

 

Solitary laboratory work in the early hours of the morning, hectic trips around the world, meetings and conferences in Canada, France, Denmark, the US, Chile and Brazil: welcome to the world of liver research!

 

“We try to identify pharmacological possibilities to treat liver disease. We also look for new biomarkers that would help us to improve the accuracy of diagnoses and prognoses.” Currently Vinken and his team are focusing on the small channels alongside the cell plasma membrane.

 

It’s all about cell communication

Our body’s many cells communicate with each other using channels called gap junctions. A gap junction is formed by hemichannels, or connexons, pores in the cell membrane of each adjoining cell. Each connexon is constructed from six connexin proteins.

 

Gap junctions control and ensure the communication necessary for the many of our cells’ regular and critical maintenance procedures.

"We're trying to improve the accuracy of diagnoses and prognoses of liver disease"

Until the end of the 1990s it was understood that gap junctions were open during good health (making communication possible) and closed during disease (preventing communication and impacting cell functionality). However, it was subsequently discovered that in the diseased state an individual connexon can open independently, thereby enabling a cell to communicate directly with the extracellular space. This discovery also led to the identification of new structures called pannexins, the proteins that form these individual transmembrane channels. Pannexins strongly resemble connexin proteins, and seem to be primarily, though certainly not uniquely, active during disease.

 

“The discovery of the novel functioning of connexons and newly identified pannexin proteins created quite a stir in our research field. Yet there is still much that we do not understand about pannexins, mainly because we lack the technology to examine them closely. What is the exact purpose of these tiny channels? Which substances and mechanisms stimulate or inhibit their activities?”

 

Vinken and his team were the first to demonstrate that some cell channels are open during the livercelldeath process, a key trigger of many liver diseases. They are now working on developing substances that can act specifically to close the individual hemichannels without impacting gap junctions. If successful, the generic principle of closing ‘bad’ channels and opening ‘good’ ones will have a substantial impact on research into diabetes, heart disease, cancer…

 

Recognition for a top European researcher

These remarkable findings are not purely the result of laboratory work; they are also about ‘thinking outside the box’ and networking. Then there’s the role of funding.

 

In 2013, Vinken was awarded a 1.47 million euro Starting Grant from the European Research Council (ERC).  It wasn’t an instant result. In June 2013, the reviewers of Vinken’s application bluntly confronted him with the shortcomings of his CV, putting him at the top of the reserve list. “They were positive about my large scientific output, but highlighted a lack of independence and mobility. It turns out I made an error in not working in a foreign lab for an extended period during my doctorate and post-doc years. Apart from the volume of publications, mobility has become one of the major parameters used to screen a scientific CV.”

"I still get goose bumps just thinking about that moment"

Although the first reserves usually do receive a grant, it is not a foregone conclusion. But Vinken got lucky: one fine day a message dropped into his mailbox, “We are now in the position to start the ERC granting procedure. I still get goose bumps just thinking about that moment. The Starting Grant enabled me to hire four assistants and buy equipment. That’s why, contrary to many other labs, we haven’t had to abandon tests due to lack of funds. I’m only too aware that this is a rare privilege and that it can all change quickly. One way or another it turns out that ERC funding is a key asset on one’s CV. I’ve enjoyed an incredible snowball effect since then.”

 

Networking around the globe

Shortly before substantial grants made his scientific work possible, Vinken secured contacts: yet another major trump card in the scientific world. Research nowadays often occurs simultaneously in different places. Active networking, coincidences and luck can bring projects together. That’s how great science works ‑ and Mathieu Vinken knows it!

 

“As an in vitro lab, we mainly have to base our findings on tests with liver cells in cell culture dishes. We are always faced with the question of whether cells in a dish are truly representative of an entire liver, a living animal, let alone a human being. By chance, a Brazilian in vivo lab, which works with animals and is active in exactly the same research area, was asking the reverse question. Many factors can affect animal testing: with in vitro research we have far better control over the parameters. Just when I was looking for someone with in vivo expertise in 2012, the Universidade de São Paulo (USP) approached us for in vitro expertise. ”

 

The Brussels and São Paulo projects turned out to be broadly complementary and this led to an invitation from the Brazilian research group. Since 2013 and until 2018 Vinken spends three months a year as visiting professor at USP.

 

The day-to-day coordination of two research teams on different continents, mostly supported by Skype and e-mail, is quite a challenge. “I’m someone who likes to get a move on. Everything must be structured, quick and efficient which is not how things work in Brazil!” Vinken smiles, “I have to reset my brain each time I go there. People live and work differently in Brazil.”

 

The Brazil experience has nevertheless proved to Vinken that networking is the way to get ahead in the scientific world. “I travel globally both to initiate collaborative ventures and to attend conferences. For a scientist, this is just as important as publishing.”

 

Surfing the wave of success

Money breeds money in the same way that success breeds success. Vinken is surfing the biggest waves he can find. In 2013 the Flemish Fund for Scientific Research gave the go-ahead to two of his project applications. In addition, the São Paulo Research Foundation awarded him a São Paulo Excellence Chair, which came with a grant of about 700,000 euro and enabled him to expand his Brazilian team. This team now consists of two post-docs, two post-grads and two bursary students. Three VUB doctoral students also carry out research at USP in Brazil three months each year, which will result in a double VUB-USP PhD diploma.

 

Vinken is currently also working on an application for a European Cooperation in Science and Technology (COST) Action involving more than 100 partners from 22 European countries, the US, Canada, New Zealand, Singapore and Brazil. “Connexin and pannexin research is happening throughout the world and we really need a European research network.”

 

Early findings and technology transfer

The hard work and energy Vinken has invested in filling in application forms, travelling around the world, setting up teams and connecting scientific research projects is beginning to pay off. The preliminary outcomes of the animal experiments at USP confirm the in vitro tests at VUB. “When we administer substances that close the connexin and pannexin channels in mice with a diseased liver, the disease is suppressed.”

"Recently we have started testing liver samples from human patients"

The next step is to determine the extent to which this applies to humans. “To find out, we try to simulate reality as closely as possible. Recently we have started to test liver samples from human patients with liver disease. We are collaborating with the University Hospital of São Paulo and the General City Hospital in Aalst for this.”

 

Vinken also got in touch with Zealand Pharma in Denmark, one of the only pharmaceutical companies working on connexin and pannexin channels. “I’m really pleased with this first step towards technology transfer. Ultimately, you have to do something useful with the end result. Though it’s true that we’ve only just got the first test results, you have to act as quickly as possible where patents are concerned.”

 

Getting out there

“Go abroad!” Vinken advises young PhD students who are looking to stay in research. “Mainly because you will find expertise that is lacking in Belgium, but also because it will give you the chance to mature: it’s your first step towards independence. Two years ago, one of the PhD students I am supervising left for Brazil as a newly graduated kid; he returned as a man. A foreign experience like that helps you to develop and mature as a person.”